Mehdi Rashighi

Simvastatin prevents and reverses depigmentation in a mouse model of vitiligo

Vitiligo is a common autoimmune disease of the skin that results in disfiguring white spots. There are no FDA-approved treatments, and current treatments are time-consuming, expensive, and have low efficacy. We sought to identify new treatments for vitiligo, and first considered repurposed medications because of the availability of safety data and expedited regulatory approval. We previously reported that the IFN-γ-induced chemokine CXCL10 is expressed in lesional skin from vitiligo patients, and that it is critical for the progression and maintenance of depigmentation in our mouse model of vitiligo. We hypothesized that targeting IFN-γ signaling might be an effective new treatment strategy. STAT1 activation is required for IFN-γ signaling and recent studies revealed that simvastatin, an FDA-approved cholesterol-lowering medication, inhibited STAT1 activation in vitro. Therefore, we hypothesized that simvastatin may be an effective treatment for vitiligo. We found that simvastatin both prevented and reversed depigmentation in our mouse model of vitiligo, and reduced the number of infiltrating autoreactive CD8+ T cells in the skin. Treatment of melanocyte-specific, CD8+ T cells in vitro decreased proliferation and IFN-γ production, suggesting additional effects of simvastatin directly on T cells. Based on these data, simvastatin may be a safe, targeted treatment option for patients with vitiligo.

Suction blistering the lesional skin of vitiligo patients reveals useful biomarkers of disease activity

Background: Vitiligo is an autoimmune disease of the skin with limited treatment options; there is an urgent need to identify and validate biomarkers of disease activity to support vitiligo clinical studies. Objective: To investigate potential biomarkers of disease activity directly in the skin of vitiligo subjects and healthy subjects. Methods: Patient skin was sampled via a modified suction‐blister technique, allowing for minimally invasive, objective assessment of cytokines and T‐cell infiltrates in the interstitial skin fluid. Potential biomarkers were first defined and later validated in separate study groups. Results: In screening and validation, CD8+ T‐cell number and C‐X‐C motif chemokine ligand (CXCL) 9 protein concentration were significantly elevated in active lesional compared to nonlesional skin. CXCL9 protein concentration achieved greater sensitivity and specificity by receiver operating characteristic analysis. Suction blistering also allowed for phenotyping of the T‐cell infiltrate, which overwhelmingly expresses C‐X‐C motif chemokine receptor 3. Limitations: A small number of patients were enrolled for the study, and only a single patient was used to define the treatment response. Conclusion: Measuring CXCL9 directly in the skin might be effective in clinical trials as an early marker of treatment response. Additionally, use of the modified suction‐blister technique supports investigation of inflammatory skin diseases using powerful tools like flow cytometry and protein quantification.

Understanding autoimmunity of vitiligo and alopecia areata.

Purpose of review Vitiligo and alopecia areata are common, disfiguring skin diseases. Treatment options are limited and include nontargeted approaches, such as corticosteroids, topical calcineurin inhibitors, narrow band ultraviolet B phototherapy, and other immune-modifying agents. The purpose of this article is to review shared, novel mechanisms between vitiligo and alopecia areata, as well as discuss how they inform the development of future targeted treatments. Recent findings Vitiligo and alopecia areata are both autoimmune diseases, and striking similarities in pathogenesis have been identified at the level of both the innate and adaptive immune system. Increased reactive oxygen species and high cellular stress level have been suggested as the initiating trigger of the innate immune system in both diseases, and genome-wide association studies have implicated risk alleles that influence both innate and adaptive immunity. Most importantly, mechanistic studies in mouse models of vitiligo and alopecia areata have specifically implicated an interferon (IFN)&ggr;-driven immune response, including IFN&ggr;, IFN&ggr;-induced chemokines, and cytotoxic CD8+ T cells as the main drivers of disease pathogenesis. These recent discoveries may reveal an effective strategy to develop new treatments, and several proof-of-concept clinical studies support this hypothesis. Summary The identification of IFN&ggr;-driven immune signaling pathways has enabled discoveries of potential new treatments for vitiligo and alopecia areata, and supports initiation of larger clinical trials.

Vitiligo Pathogenesis and Emerging Treatments

The pathogenesis of vitiligo involves interplay between intrinsic and extrinsic melanocyte defects, innate immune inflammation, and T-cell-mediated melanocyte destruction. The goal of treatment is to not only halt disease progression but also promote repigmentation through melanocyte regeneration, proliferation, and migration. Treatment strategies that address all aspects of disease pathogenesis and repigmentation are likely to have greatest efficacy, a strategy that may require combination therapies. Current treatments generally involve nontargeted suppression of autoimmunity, whereas emerging treatments are likely to use a more targeted approach based on in-depth understanding of disease pathogenesis, which may provide higher efficacy with a good safety profile.

Interfering with the IFN-γ/CXCL10 pathway to develop new targeted treatments for vitiligo.

Vitiligo is a common, disfiguring autoimmune disease caused by the destruction of epidermal melanocytes. It presents with patchy depigmentation of skin, which significantly affects patients’ self-esteem and quality of life. The mainstay of vitiligo treatment is topical steroids, calcineurin inhibitors, and/or narrow band UVB (nbUVB) phototherapy ( 1 ). These treatments utilize a non-targeted approach with moderate efficacy, but are used off-label, as they are not Food and Drug Administration (FDA)-approved for use in vitiligo. Currently, the only FDA-approved treatment for the disease is monobenzone cream (Benoquin ® ), which is actually used to permanently depigment, rather than repigment, the skin. This treatment results in an even skin tone, and can be appropriate for patients with extensive disease ( 2 , 3 ). However, it is one of a limited number of treatments used in medicine to intentionally make disease worse, and treatments focused on reversing vitiligo, with better efficacy, are greatly needed.

Melanocytes in psoriasis: convicted culprit or bullied bystander?

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